抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

“Bioinformatics” 특집을 내면서

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(11)61452-9.pdf

Selenium and human health

In the genetic code, UGA serves as a stop signal and a selenocysteine codon, but no computational methods for identifying its coding function are available. Consequently, most selenoprotein genes are misannotated. We identified selenoprotein genes in sequenced mammalian genomes by methods that rely on identification of selenocysteine insertion RNA structures, the coding potential of UGA codons, and the presence of cysteine-containing homologs. The human selenoproteome consists of 25 selenoproteins.

/pdf/characterization-of-mammalian-selenoproteomes-296pbto9lm.pdf

Characterization of Mammalian Selenoproteomes

Tetraodon nigroviridis is a freshwater puffer fish with the smallest known vertebrate genome. Here, we report a draft genome sequence with long-range linkage and substantial anchoring to the 21 Tetraodon chromosomes. Genome analysis provides a greatly improved fish gene catalogue, including identifying key genes previously thought to be absent in fish. Comparison with other vertebrates and a urochordate indicates that fish proteins have diverged markedly faster than their mammalian homologues. Comparison with the human genome suggests ∼900 previously unannotated human genes. Analysis of the Tetraodon and human genomes shows that whole-genome duplication occurred in the teleost fish lineage, subsequent to its divergence from mammals. The analysis also makes it possible to infer the basic structure of the ancestral bony vertebrate genome, which was composed of 12 chromosomes, and to reconstruct much of the evolutionary history of ancient and recent chromosome rearrangements leading to the modern human karyotype.

/pdf/genome-duplication-in-the-teleost-fish-tetraodon-qw9iuo5jxx.pdf

Genome duplication in the teleost fish Tetraodon nigroviridis reveals the early vertebrate proto-karyotype

Selenium is an essential micronutrient in the diet of many life forms, including humans and other mammals. Significant health benefits have been attributed to this element. It is rapidly becoming recognized as one of the more promising cancer chemopreventive agents (19), and there are strong indications that it has a role in reducing viral expression (4), in preventing heart disease and other cardiovascular and muscle disorders (23), and in delaying the progression of AIDS in human immunodeficiency virus-infected patients (3). Additional evidence suggests that selenium may have a role in mammalian development (51), in immune function (70), in male reproduction (30), and in slowing the aging process (70).

Despite the many potential health benefits of selenium, the means by which this element promotes better health are only just beginning to be elucidated (31, 91). There are about 20 known selenium-containing proteins in mammals (33), and it would seem very likely that several of these are mediators of health benefits of dietary selenium. Therefore, it is critical to understand how selenium is inserted into protein and the identities and functions of the resulting protein products. Selenium is present in naturally occurring selenium-containing proteins in two basic forms. It can be inserted posttranslationally as a dissociable cofactor (32). This rare form of protein-associated selenium has been found only in several bacterial molybdenum-containing enzymes and will not be discussed further in this review. Selenium is also cotranslationally inserted into protein as the amino acid selenocysteine (Sec). Such occurrence of this element in protein is widespread in all major domains of life and is responsible for the majority of biological effects of selenium. The elucidation of how Sec is incorporated into protein has progressed at a rapid pace in the last decade and has revealed some surprising results. In fact, unraveling this mystery has altered our understanding of the genetic code, as the code has now been expanded to include Sec as the 21st naturally occurring amino acid. When the code was deciphered in the mid-1960s (48, 79), 20 amino acids were assigned to 61 of the possible 64 codons within the triplet code and 3 codons were found to function as terminators for protein synthesis. Each of the 64 code words was therefore assigned a function, and there did not appear to be room for additional amino acids. Although it was recognized in the mid-1960s that one code word, AUG, had a dual role of initiating protein synthesis and inserting methionine at internal protein positions, the possibility that a second codon also had two functions was not considered at that time. We now know that UGA serves as both a termination codon and a Sec codon. The means by which UGA serves as a Sec codon and how Sec is biosynthesized and incorporated into protein have been examined in considerable detail with eubacteria (reviewed in reference 7) and with mammals (this review). While the fundamental mechanism of Sec insertion in these organisms appears to be similar, recent studies suggest that mammals evolved additional components that allow incorporation of multiple Secs into a single protein and provide stringent regulation of Sec biosynthesis. The present review discusses our current knowledge of these features in mammals.

It should be noted that selenium can also be incorporated nonspecifically into protein (42). The nonspecific occurrence of this element in protein arises when selenium replaces sulfur in the biosynthesis of cysteine or methionine and the resulting selenoamino acid (Sec or selenomethionine) is inserted in place of the natural amino acid. Such misincorporation of selenium into protein may be toxic; this subject has been reviewed elsewhere (42).

How selenium has altered our understanding of the genetic code.

List of Contributors. Foreword R.F. Burk. Preface D.L. Hatfield. Acknowledgements.1. Introduction D.L. Hatfield. Part I: Biosynthesis of selenocysteine and its incorporation into protein: 2. Selenium metabolism in bacteria A. Bock. 3. Mammalian selenocysteine tRNA B.A. Carlson, et al. 4. Selenophosphate selenium donor for protein and tRNA G.M. Lacourciere. 5. SECIS elements G.W. Martin III, M.J. Berry. 6. SECIS binding proteins P.R. Copeland, D.M. Driscoll. 7. Towards a mechanism for selenocysteine incorporation in eukaryotes J.B. Mansell, M.J. Berry. 8.Regulation of selenoprotein expression R.A. Sunde. Part II: Selenium-containing proteins: 9. Identity, evolution and function of selenoproteins and selenoprotein genes V.N. Gladyshev. 10. Bacterial selenoenzymes and mechanisms of action T.C. Stadtman. 11. Selenoprotein P K.E. Hill, R.F. Burk. 12. Selenoprotein W: A muscle protein in search of a function L. Walt Ream, et al. 13. The 15 kDa selenoprotein (Sep15): functional studies and a role in cancer etiology V.N. Gladyshev, et al. 14. Selenoproteins of the glutathione system L. Flohe, R. Brigelius-Flohe. 15. Selenoproteins of the thioredoxin system A. Holmgren. 16. Selenium, deiodinases and endocrine function D.L. St. Germain. Part III: Selenium and human health: 17. Selenium as a cancer preventive agent G.F. Combs Jr., Junxuan Lu. 18. Selenium deficiency and human disease R.Th.J. Coppinger, A.M. Diamond. 19. Selenium as an antiviral agent M.A. Beck. 20. Role of selenium in HIV/AIDS M.K. Baum, et al. 21. Effects of selenium on immunity and aging R.C. McKenzie, et al. 22. Selenium and male reproduction L. Flohe, et al. 23. Role of low molecular weight, selenium-containing compounds in human health H.J. Thompson. 24. Evolution of human dietary standards for selenium O.A. Levander. 25. Selenium in Biology and human health: controversies and perspectives V.N. Gladyshev. Index.

Selenium: Its Molecular Biology And Role In Human Health

Selenocysteine (Sec) is cotranslationally inserted into protein in response to UGA codons and is the 21st amino acid in the genetic code. However, the means by which Sec is synthesized in eukaryotes is not known. Herein, comparative genomics and experimental analyses revealed that the mammalian Sec synthase (SecS) is the previously identified pyridoxal phosphate-containing protein known as the soluble liver antigen. SecS required selenophosphate and O-phosphoseryl-tRNA[Ser]Sec as substrates to generate selenocysteyl-tRNA[Ser]Sec. Moreover, it was found that Sec was synthesized on the tRNA scaffold from selenide, ATP, and serine using tRNA[Ser]Sec, seryl-tRNA synthetase, O-phosphoseryl-tRNA[Ser]Sec kinase, selenophosphate synthetase, and SecS. By identifying the pathway of Sec biosynthesis in mammals, this study not only functionally characterized SecS but also assigned the function of the O-phosphoseryl-tRNA[Ser]Sec kinase. In addition, we found that selenophosphate synthetase 2 could synthesize monoselenophosphate in vitro but selenophosphate synthetase 1 could not. Conservation of the overall pathway of Sec biosynthesis suggests that this pathway is also active in other eukaryotes and archaea that synthesize selenoproteins.

/pdf/biosynthesis-of-selenocysteine-on-its-trna-in-eukaryotes-44mzn2pb4g.pdf

Biosynthesis of selenocysteine on its tRNA in eukaryotes.

Selenium has cancer protective effects in a variety of experimental systems. Currently, it is not known whether selenoproteins or low molecular weight selenocompounds are responsible for this activity. To evaluate the contribution of selenoproteins to the cancer protective effects of selenium, we used transgenic mice that carry a mutant selenocysteine transfer RNA gene, which causes reduced selenoprotein synthesis. Selenium homeostasis was characterized in liver and colon of wild-type and transgenic mice fed selenium-deficient diets supplemented with 0, 0.1, or 2.0 microg selenium (as selenite)/g diet. (75)Se-labeling, Western blot analysis, and enzymatic activities revealed that transgenic mice have reduced (P < 0.05) liver and colon glutathione peroxidase expression, but conserved thioredoxin reductase expression compared with wild-type mice, regardless of selenium status. Transgenic mice had more (P < 0.05) selenium in the nonprotein fraction of the liver and colon than wild-type mice, indicating a greater amount of low molecular weight selenocompounds. Compared with wild-type mice, transgenic mice had more (P < 0.05) azoxymethane-induced aberrant crypt formation (a preneoplastic lesion for colon cancer). Supplemental selenium decreased (P < 0.05) the number of aberrant crypts and aberrant crypt foci in both wild-type and transgenic mice. These results provide evidence that a lack of selenoprotein activity increases colon cancer susceptibility. Furthermore, low molecular weight selenocompounds reduced preneoplastic lesions independent of the selenoprotein genotype. These results are, to our knowledge, the first to provide evidence that both selenoproteins and low molecular weight selenocompounds are important for the cancer-protective effects of selenium.

Both Selenoproteins and Low Molecular Weight Selenocompounds Reduce Colon Cancer Risk in Mice with Genetically Impaired Selenoprotein Expression

https://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1094&context=biochemgladyshev

Comparative analysis of selenocysteine machinery and selenoproteome gene expression in mouse brain identifies neurons as key functional sites of selenium in mammals.

Dolph L. Hatfield

Papers

How selenium has altered our understanding of the genetic code.

Selenium: Its Molecular Biology And Role In Human Health

Biosynthesis of selenocysteine on its tRNA in eukaryotes.

Both Selenoproteins and Low Molecular Weight Selenocompounds Reduce Colon Cancer Risk in Mice with Genetically Impaired Selenoprotein Expression

Comparative analysis of selenocysteine machinery and selenoproteome gene expression in mouse brain identifies neurons as key functional sites of selenium in mammals.